Citation or identification of any reference herein, or any section of this application shall not be construed as an admission that such reference is available as prior art to the present application. The disclosures of each of these publications in their entireties are hereby incorporated by reference in their entirety in this application, and shall be treated as if the entirety thereof forms a part of this application.
Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic, human insulin, 25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. (Leader et al., 2008, Protein therapeutics: a summary and pharmacological classification Nature Reviews Drug Discovery 7, 21-39).
Targeted monoclonal antibodies comprise a major form of therapeutic proteins. Targeting monoclonal antibodies to the tumor can result in the destruction of the tumor cells by antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Similarly, targeting cytokines or immunomodulatory molecules either by bispecific scFv or antibody—ligand fusion proteins to the tumor modulates the immune response against the tumor. In addition, antibody-ligand fusion proteins can induce apoptosis to targeted cells as well as bystander cells by, for example, presenting FasL. A more direct approach to kill the targeted cell is the conjugation of cytotoxic drugs, toxins or radionucleotides to the monoclonal antibodies. The antibody-directed enzyme prodrug therapy (ADEPT) approach specifically aims at causing bystander effects by targeting enzymes to the tumor cell and delivering a prodrug that is converted to a chemotherapeutic by the targeted enzyme. (Schrama et al., 2006, Antibody targeted drugs as cancer therapeutics, Nature Reviews Drug Discovery 5, 147-159). Examples of monoclonal antibody therapeutics are shown in Table I. However, means to enhance their protease stability have not been provided, particularly for tumor-targeted antibodies.
TABLE IMonoclonal antibody therapeutics approved for clinical use. From: An, 2008, Antibody Therapeutics—a mini review. Trends in Bio/Pharmaceutical Industry 2: 24-29.Generic NameTrade NameLaunchTherapyMajorProteinRefer-ManufacturerDateAreaIndicationTargetForm/IsotypeDeliveryenceMuromonab1986AIIDTransplant CD3Murine IgG2aIV(16)Orthoclone/OKT3rejectionJohnson & JohnsonAbciximab1995CVCardiovascularCD41Chimeric FabIV (8)ReoProdiseaseEli LillyRituximab1997OncologyNon-Hodgkin'sCD20Chimeric IgG1IV(17)Rituxan/MabTheraLymphomaGenentech/RocheDaclizumab1997AIIDTransplantCD25Humanized IgG1IV (9)ZenapaxrejectionRocheBasiliximab1998AIIDTransplantCD25Chimeric IgG1IV(18)SimulectrejectionNovartisInfliximab1998AIIDRheumatoidTNF alphaChimeric IgG1IV(19)RemicadearthritisCentocorPalivizumab1998IDRespiratoryRSVChimeric IgG1IM(20)Synagissyncytial virusF-proteinMedImmuneTrastuzumab1998OncologyBreast cancerHcr2HumanizedIV(21)HerceptinIgG1GenentechGemtuzumab/ozo-2000OncologyAcute myclog-CD33Humanized IgG4IV(22)gamicinenous leukemiaconjugated withMylotargozogamicinWyethAlemtuzumab2001OncologyChronicCD52HumanizedIV(23)CampathlymphocyticIgG1Bayer-ScheringleukemiaIbritumomab2002OncologyNon-Hodgkin'sCD20Murine IgG1IV(24)tiuxetanLymphomaconjugated withZevalinYttrium 90Biogen/IdecOmalizumab2003RespiratoryAsthmaIgEHumanizedSC(25)XolairIgG1Genentech/NovartisEfalizumab2003AIIDPsoriasisCD11AHumanizedSC(26)RaptivaIgG1GenentechTositumomab2003OncologyNon-Hodgkin'sCD20Murine IgG2aIV(27)BexxarLymphomaconjugated withGSKIodine-131Adalimumab2003AIIDRheumatoidTNF alphaHuman IgG1SC(11)HumiraarthritisAbbottCetuximab2003OncologyColorectalEGFRChimeric IgG1IV(28)ErbituxcancerImClone/BMSI-131 ch-TNT2003OncologyAdvanced lungIntracellularChimeric IgG1IV(29)Shanghai MedipharmcancerDNA inconjugated withBiotech Co.tumorsI-131Bevacizumab2004OncologyColorectal and VEGFHumanizedIV(30)Avastinnon-small cellIgG1Genentechlung cancerNatalizumab2004CNS/AIIDMultipleVLA4humanized IgG1IV(31)TysabrisclerosisBiogen IDEC/ElanTocilizumab2005AIIDCastleman'sIL-6RHumanized IgG1IV(32)ActemradiseaseRoche/ChugaiRanibizumab2006Ophthal-Wet age-relatedVEGFHumanized mabInjection (3)Lucentismologymacular fragment ofinto the Genentech/NovartisdegenerationAvastineyePanitumumab2006OncologyColorectalEGFRHuman IgG2IV(33)VectibixcancerAmgenCertolizumab pegol2007AIIDRheumatoidTNF alphaPEGylatedSC (4)CimziaarthritisFragment UCB-SchwarzEculizumab2007HematologyPNH (chronicC5aHumanizedIV(34)Solirishemolysis)IgG2/IgG4Alexionhybrid